In-use stability and compatibility studies are an important aspect of drug development and are required already in early phase clinical studies. The aim of such studies is to investigate the stability of investigational medicinal product (IMP) in a pharmacy/clinical setting and at the same time investigate the compatibility of the drug with the different contact materials used in the preparation and administration of the IMP.

Preparation 

In biologic pharmaceuticals the investigational drug or IMP is often a parenteral solution, either a liquid or a lyophilized product requiring reconstitution. Different ways of administration are used but most often it is through intravenous (IV) or subcutaneous (SC) injection. In many occasions the IMP needs some kind of preparation at the hospital pharmacy before it is can be administrated to the patient. Very often this involves reconstitution, predilution, or some other kind of handling bringing the product in a different environment from its original formulation and primary pack. 

Contact Materials

Next to preparation,  administration involves the product getting in contact with different kind of materials, frequently plastics which are used in items such as IV bags, syringes, IV lines, etc. As for these articles, there are numerous different brands available on the market some pre-study is required. One important aspect to consider is in which continent you plan to run your clinical studies. For example, PVC IV bags are typically used in the US whereas Europe typically uses polypropylene or polyethylene bags. The same story for IV lines and filters, EU clinics often use an infusion line with a drip chamber containing a filter whereas in the US this is less common. Once you have established the list of contact materials you want to investigate you can set up your study. An experimental design may be considered to reduce the number of combinations to be tested but still get a reliable outcome.

Dosing

In early phase clinical development the effective dose is most often unknown. Phase 1 studies typically have a dose escalating scheme starting at a relative low dose escalating to higher doses which are sometimes 100-fold higher or more. To prevent the experiment size running out of control a bracketing approach may be used in which doses at the low end and at the high end are studied assuming the high dose is known. All doses between the low and high end are then covered. 

In-use Stability & Compatibility Study

The study itself consists of different parts:

1. Authoring of the study plan or protocol in which you clearly describe the aim of the study, the doses and materials to be studied, the analytics used for evaluation and the acceptance criteria.
2. IMP preparation. A downscale model may be considered to save drug material and time to run the experiment, eg one could consider using a 50 mL IV bag relative to a 250 mL IV bag used in the clinic.
3. IMP storage before administration, determine how much time is required to prepare the dose and how much time is typically needed before administration starts. Some countries also demand administration time to be included. The time studied should cover all of these and preferably a bit more. Also determine if the prepared IMP can be stored at room temperature and exposed to daylight or if it needs cold storage and/or protection from light.
4. Administration simulation. After IMP preparation and storage, the IMP administration should be mimicked, typically by using an IV pump device to transfer the contents of the IV bag through an IV line into a collection container. The time it takes to get a complete IV dose administered should be simulated. If a downscale model is used the downscale factor should be taken into account.
5. Analysis of administered IMP. After administration is completed the product in the collection container should be tested on content and on quality. Especially at low dosing adsorption of the IMP to the container could be a concern. Pre-studies are recommended to see if additives (eg detergents like polysorbate 80) are required to prevent unwanted loss of product or prevent particle formation. Also when operating at low product concentrations, UV absorbance or HPLC may lack the required sensitivity and specifically developed analytics may need to be developed. Product quality may be studied at quality attributes normally associated with drug product stability studies, eg appearance, visible and subvisible particles, aggregates, charge variants and potency. Again, protein concentration may be a limiting factor to the extent the quality can be assessed.
6. Evaluation of data. Once all analytical data have been collected and evaluated a conclusion can be drawn on the compatibility of the drug with the various contact materials at different doses and the stability during storage and administration. This information can then be reported and summarized in the pharmaceutical development section of the common technical document and subsequently in the pharmacy manual 

Microbial challenge study

If the drug product is a single-use presentation, it probably does not contain a preservative agent. Although the IMP is prepared under aseptic conditions, health authorities often require a supporting microbial challenge study if the prepared IMP is planned to be stored for more than four hours at room temperature prior to administration. The design of such a study uses the principles of USP<51> and the execution requires specific microbial knowledge and dedicated facilities to work in.

If you need help in setting up your initial in-use stability/compatibility studies please feel free to contact us.

References

American Pharmaceutical Review

ASHP

Google Results

https://www.casss.org/papers-and-presentations/resource/Microbial-Challenge-In-use-Studies-Industry-efforts-to-harmonize-strategies-in-collaboration-with-Health-Authorities

https://www.casss.org/docs/default-source/cmc-strategy-forum-north-america/2024-speaker-presentations/kirwan-j.-paul-amgen-inc.-2024.pdf?sfvrsn=ba22638f_4

https://pubmed.ncbi.nlm.nih.gov/37160227/